SUMMARY Resistance to Immune Checkpoint Blockade (ICB) and failure to develop durable immunity after partial responses may occur through intrinsic or acquired mechanisms. Mechanistic details and clinical correlates on how cancer escapes ICB are lacking. In previous work, we discovered that resistance to combination ICB therapy consisting of radiation (RT) and anti-CTLA4 can occur with upregulation of PDL1. This is associated with increased expression of interferon-stimulated genes (ISGs). Our preliminary data reveal a key role for tumor-intrinsic resistance mechanisms driven by prolonged interferon (IFN) signaling and related to tumor burden. Moreover, recent clinical results define a link between tumor burden and efficacy of ICB revealed by changes in exhausted T cells (TEX). We have found critical transcriptional and epigenetic events in both tumor cells and responding TEX that may reveal PDL1-independent mechanisms of resistance that are driven by prolonged IFN signaling and tumor burden. To complement parallel clinical trials that test the combination of RT + ?CTLA4 + ?PD1 in patients with advanced cancer, this project seeks to investigate PDL1-independent resistance mechanisms by examining both tumor cells and T cells. We will test the hypothesis that tumor burden and prolonged IFN signaling lead to reciprocal genomic/epigenomic changes in both cell types that limit the efficacy of RT + ?CTLA4 + ?PDL1/PD1, and that the reversibility of these genomic/epigenomic changes impacts the efficacy and durability of responses. By integrating pre-clinical and clinical efforts, our goal is to understand how IFN, a major signal in the tumor microenvironment, can paradoxically drive additional but targetable immune checkpoint pathways to control T cell exhaustion and resistance to combination therapy. In so doing, we will inform the design of the next generation of clinical trials by focusing on underlying determinants of durable response.